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Copyright 2008, Arno Kumagai, Gary Hammer
The following information is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. You should speak to your physician or make an appointment to be seen if you have questions or concerns about this information or your medical condition. You assume all responsibility for use and potential liability associated with any use of the material.
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Logo: All Rights Reserved Regents of the University of Michigan.
2008 Gary D. Hammer, M.D., Ph.D. University of Michigan Ann Arbor, Michigan USA Learning Objectives
After this lecture you should have an understanding of:
• The feedback loops regulating cortisol secretion.
• The physiologic actions of glucocorticoids (cortisol) + mineralocorticoids (aldosterone)
• The major pharmacologic uses of glucocorticoids.
• The major types of glucocorticoids.
• The major side effects of glucocorticoid therapy. Anatomy of the adrenal glands
Public Domain Wikimedia Commons
Public Domain Seers.gov
Public Domain Wikimedia Commons Histology of the Adrenal Gland
adrenal cortex
CC:BY-NC-SA 1.0 BY: Royal College of Surgeons of Ireland (RCSI)
adrenal medulla
Public Domain Wikimedia Commons Adrenocortical Hormones = Steroids
GLUCOCORTICOID MINERALOCORTICOID Cortisol Aldosterone
cortex medulla
Adrenal Steroidogenesis
glomerulosa
fasciculata
reticularis
gonad periphery
Public Domain Wikimedia Commons ‘Roids: The Bottom Line
In the right amounts, steroids can be the body’s best friend….
or in the wrong amounts, the body’s worst enemy…. Role of Glucocorticoids in Human Physiology
In the right amounts, glucocorticoids keep:
• Your blood pressure up (maintain cardiovascular stability).
• Your blood sugar up (maintain metabolic homeostasis).
• Your disposition sunny (maintain integrity of CNS function).
• Your temperament cool (regulate response to stress). Adrenocortical Hormones = Steroids
GLUCOCORTICOID MINERALOCORTICOID Cortisol Aldosterone
cortex medulla
Adrenal The HPA axis
Neural Stimuli Hypothalamus -- CRF ++ ACTH Anterior Pituitary --
ACTH Plasma Cortisol Concentration
Adrenal ++
CC:BY 3.0 BY: Regents of the University of Michigan Regulation of ACTH Expression by CRH
Public Domain Bruno Dubuc Post-translational Processing of POMC in the Normal Pituitary
POMC = Pro-opiomelanocortin
ACTH
Source: Undetermined MSH = Melanocyte stimulating hormone ACTH and Steroid Biosynthesis
POLYSOME CELL MEMBRANE ATP 3',5' cAMP INACTIVE PROTEIN PROTEIN ACTH ADENYLATE CYCLASE KINASE
ACTIVE PROTEIN
CHOLESTEROL ESTER STEROID CHOLESTEROL BIOSYNTHESIS Secretion, Transport and Metabolism of Cortisol
Image of CNS Control removed Circadian Rhythm of Cortisol Secretion
Highest in morning
24 hour period 24 hour period day night day night 20 g/100 ml
μ 15
10
5 Plasma Cortisol Cortisol Plasma
0 8 AM 4 PM 12 MID 8 am 4 PM 12 MID
Source: Undetermined Lowest in evening Corticosteroid Binding Globulin (CBG)
Image of Globulin removed
SHBG Grishkovskaya et al, 1999
• Acidic glycoprotein MW 52,000 • Produced in liver, lung, kidney, testes • Regulates delivery of cortisol to tissues Conditions that Affect Cortisol Metabolism
• Increased Turnover: --Thyroxine --Barbiturates --Phenytoin
• Decreased Turnover: --Liver disease
• Increased Binding: --Estrogens Molecular Action of Glucocorticoids
Glucocorticoid receptors (GR) are transcriptional activators of a variety of gene products.
Image of Glucocorticoid Target Cell removed Metabolic Effects of Glucocorticoids
Prototypical Glucocorticoid = Cortisol
Glucocorticoids Insulin
Glucocorticoids effects are generally opposite those of insulin. Glucocorticoids & Carbohydrate Metabolism
GLUCOCORTICOIDS Glucocorticoids increase hepatic (+) Glucocorticoids glucose output decrease insulin sensitivity (-) Liver Glucose (-) MUSCLE
(+) INSULIN
FAT CELL Glucocorticoid Effects on Protein Metabolism
Insulin Glucocorticoids
Anabolism (storage) Catabolism MUSCLE Protein synthesis Protein synthesis Protein breakdown Protein breakdown Amino acid release Amino acid release Glucocorticoid Effects on Lipid Metabolism
Insulin Glucocorticoids
Anabolism (storage) Catabolism Lipid synthesis Lipid synthesis Lipolysis ADIPOCYTE Lipolysis Fatty acid release Fatty acid release
Redistribution of fat Redistribution of Fat in Glucocorticoid Excess
Image of patient removed
Central obesity seen in Cushing’s Syndrome (Glucocorticoid Excess) Glucocorticoid Effects on Inflammatory Mediators
Glucocorticoids INHIBIT inflammation.
Inhibit:
1) Arachidonic acid and its metabolites (prostaglandins; leukotrienes) 2) Platelet activating factor (PAF) 3) Tumor necrosis factor (TNF) 4) Interleukin-1 (IL-1) 5) Plasminogen activator Sites of Action of Glucocorticoids in the Responses of Leukocytes During Antigenic Challenge/Inflammation
Image of Glucocorticoids removed Glucocorticoids
Clinical Uses of Glucocorticoids Steroid Therapy: Routes of Administration
• Systemic Oral Parenteral
• Topical • Inhalation Clinical Uses of Glucocorticoids
• Replacement therapy
• Anti-inflammatory effect
• Immunosuppression
• Androgen suppression Glucocorticoids: Use as Anti-Inflammatory Agents
Severe RA of hands Source: Undetermined
Emily Janz, a 36-year old woman presents with a 3-year history of rheumatoid arthritis. The disease has been progressive with involvement of PIP joints in both hands, wrists, elbows and TM joints. Treatment with non- steroidal anti-inflammatory drugs (NSAIDs) has not been successful.
Treatment with prednisone is begun using an alternate-day program. Glucocorticoids: Use in Immunosuppression
CC-BY-ND 2.0 BY: wolfpix
A 25-year old man was walking through a field when he was stung by an insect. He developed generalized edema, dyspnea, wheezing and dizziness. He was rushed by a friend to the emergency room, where a diagnosis of anaphylactoid reaction to insect bite was made.
He received a large dose of steroids parenterally and was subsequently advised on a program to taper the steroids over the next one week. Glucocorticoids: Use in Immunosuppression
Heart
James Allen, a 55-year old man with a history of ischemic cardiomyopathy develops increasingly severe congestive heart failure. When he becomes totally incapacitated with a life-expectancy of less than 6 mo., he is placed on the cardiac transplantation list.
Two months later, he receives a heart and is subsequently placed on an immunosuppressive “cocktail” that includes prednisone, 5 mg daily. Glucocorticoids: Use in Androgen Suppression
Hirsutism in a young woman CC:BY-NC-SA BY: C. Matthew Peterson, MD
A 25-year old woman comes in for evaluation of hirsutism present over the past 3 years. The hirsutism is of the androgen type and is associated with acne and irregular menses. Diagnostic studies reveal elevated serum dehydroepiandrosterone (DHEA) and testosterone levels.
She receives Dexamethasone 2.0 mg daily, for seven days and serum DHEA and testosterone levels are measured the 8th day. Adrenocortical Hormones = Steroids
GLUCOCORTICOID MINERALOCORTICOID Cortisol Aldosterone
cortex medulla
Adrenal Effects of Mineralocorticoid on Renal Tubule
Prototypical mineralocorticoid = Aldosterone
Image removed
Aldosterone increases sodium resorption and potassium and hydrogen ion excretion. Prototype of Steroid Compounds
Source: Undetermined Steroids: Structure-function Relationships
A. Hydrocortisone B. Prednisone C. 9--Fluorocortisol
Source: Undetermined
• Double-bond in 1,2 position increases glucocorticoid activity. • Fluoro- group in 9-a position increases mineralocorticoid activity. Steroids
Compound Anti-Inflam. Na-Retain. Duration of Equivalent potency potency action Dose Cortisol 1 1 Short 20 mg
Prednisone 4 0.8 Intermediate 5 mg
9--fluoro- 10 125 Short * cortisone Dexa- 25 0 Long 0.75 mg methasone
Glucocorticoid effects: Dex > Prednisone > Cortisol
Mineralocorticoids: 9--fluorocortisone RULES Glucocorticoid Therapy
Side Effects
Or
“Yes, Virginia, there can be at times ‘Too Much of a Good Thing…’” Glucocorticoid Effects on Calcium & Bone
STEROIDS “BRITTLE BONES”
Osteoblastic activity Calcium absorption from gut. PTH secretion Osteoclastic activity Steroids “Brittle Bones”
A 60 yo postmenopausal woman was seen in clinic with acute onset of mid-thoracic back pain. She had complained of back pain for the past 2 years and a 2” loss of height. She had been on Prednisone, 10-15 mg daily, for the past 5 years for chronic polymyositis. Radiographic exam of the spine shows compression deformities in several vertebral bodies. CC:BY-NC-ND 2.0 BY: Wellcome Images
Public Domain NIH Chronic Glucocorticoid Therapy & Carbohydrate Metabolism
GLUCOCORTICOIDS
(+)
BLOOD (-) Liver GLUCOSE
(-) MUSCLE
(+) INSULIN
Chronic glucocorticoid therapy may “unmask” diabetes in genetically susceptible individuals. FAT CELL Glucocorticoid Effects on the Central Nervous System
caudate
hippocampus
• Neuronal death or atrophy • Structures affected: Hippocampus, caudate • Neuropsychiatric symptoms: - Cognitive- memory, learning - Mood- irritability, depression - Sleep- insomnia CC:BY-NC-ND BY: Wellcome Images “Steroid Psychosis”
A 42-yo woman with an exacerbation of lupus nephritis was treated with high-dose prednisone for several days. Her nephritis improved markedly; however, she became increasingly euphoric and severely agitated with paranoid ideation and confusion.
Following tapering of the steroid, she returned to her “usual self.” Glucocorticoid Effect on Gastric Function
STOMACH
• Secretion of HCl and pepsin • Protective barrier in the gastric mucosa
Glucocorticoid therapy may increase risk of ulcers. Complications of Chronic Exogenous Corticosteroid Use
CRH Hypothalamus (-)
ACTH Pituitary (-)
Cortisol
(+)
Adrenal Gland Complications of Chronic Exogenous Corticosteroid Use
Exogenous CRH Hypothalamus Glucocorticoid (-)
ACTH Pituitary
Cortisol
Exogenous (+) glucocorticoids suppress ACTH- stimulated cortisol secretion. Adrenal Gland Complications of Chronic Exogenous Corticosteroid Use
Exogenous CRH Hypothalamus Glucocorticoid (-)
ACTH Pituitary
ACTH is normally a trophic factor for the adrenals Cortisol
High-dose, long-term glucocorticoid use (+) results in adrenal atrophy from ACTH Adrenal suppression Gland Complications of Chronic Exogenous Corticosteroid Use
Exogenous CRH Hypothalamus Glucocorticoid
ACTH Pituitary
Cortisol Adrenal Insufficiency
(+)
Adrenal Gland Recovery of Endogenous Cortisol Secretion Following Withdrawal of Exogenous Steroids
Phase 1 Phase 2 Phase 3
HIGH RANGE
NORMAL RANGE ACTH
LOW RANGE
Source: Undetermined months 2 4 6 8 10 12 Full recovery of endogenous cortisol secretion may require up to 18 months following steroid withdrawal. Case #1
A 45-year old woman present with a two-month history of anorexia, nausea, fatigue, dizziness when assuming the upright posture, and increased pigmentation of the skin.
A diagnosis of Addison’s disease (Cortisol and Aldosterone deficiency) is confirmed by appropriate testing.
Treatment is initiated with Cortisol 25 mg. (10/10/5) and 9- fluorocortisol 0.05 mg QD. Corticosteroid Therapy Considerations
• How serious is the underlying disorder? • How long is therapy required? • What is the anticipated effective dose range? • Is patient predisposed to complications? • Which preparation to use? • Alternate day v. every day therapy. • Program for withdrawal. Complications with Prolonged Steroid Therapy
• Retarded longitudinal growth • Steroid myopathy in children* • Hypertension • GI Bleeding • Cataracts • Osteoporosis* • Psychiatric • Diabetes* • Adrenal suppression* • Cushing’s Syndrome
*Complications to remember Things to Remember if Dr. Lash put you to sleep and you’re just waking up…:
Understand:
• Feedback loops regulating cortisol secretion.
• The major physiologic actions of glucocorticoids (cortisol) and mineralocorticoids (aldosterone).
• The major pharmacologic uses of glucocorticoids.
• The major types of glucocorticoids--hydrocortisone, prednisone, dexamethasone, 9-a-fluorocortisol.
• The major side effects of glucocorticoid therapy. Adrenal Steroid Physiology & Pharmacology
Questions? DisordersDisorders ofof thethe AdrenalAdrenal CortexCortex
Logo: All Rights Reserved Regents of the University of Michigan. 2008
Gary D. Hammer, M.D., Ph.D. University of Michigan Ann Arbor, Michigan USA Goals/Objectives
Remember the basic principles of the HPA axis: homeostatic control of plasma cortisol and aldosterone levels
Remember the mechanism of action of glucocorticoids and mineralocorticoids
Understand etiology, clinical features, differential diagnosis, evaluation and therapy of 3 classic adrenal disorders:
Adrenal Insufficiency Cushing’s Syndrome Primary Hyperaldosteronism Which Twin is Sick????
Image of patients removed Adrenal Glands in Medical History
Public Domain Public Domain
Andreas Vesalius (1543) Bartholomäus Eustachius (1564) Book Five of De Corporis Humani Fabrica in 1543 glandulae quae renibus incumbent" in 1564 History of Adrenal
1716: Academie des Sciences of Bordeaux poses the question "Quel est l'usage des glandes surrenales?"
1845: French thesis on organs of Undetermined function "The adrenal cease(s) to be a secreting gland."
1855: Thomas Addison monograph “On the constitutional and local effects of disease of the supra-renal capsules,” described 10 cases marked by "anemia . . . feebleness of the heart action . . . a peculiar change of color in the skin occurring in connection with a diseased condition of the ‘suprarenal capsules'.
In 1945 Nobel Prize Kendall, Pfiffner, and Reichenstein first tested adrenal extracts on a patient with Addison's disease, and the response was prompt and striking. Anatomy of the adrenal glands
Public Domain Wikimedia Commons
Public Domain Seers.gov
Public Domain Wikimedia Commons Histology of the Adrenal Gland
adrenal cortex
CC:BY-NC-SA 1.0 BY: Royal College of Surgeons of Ireland (RCSI)
adrenal medulla
Public Domain Wikimedia Commons Adrenocortical Hormones = Steroids
GLUCOCORTICOID MINERALOCORTICOID Cortisol Aldosterone
cortex medulla
Adrenal Definition of Adrenal Insufficiency
“inappropriately low” adrenal steroid output
mineralocorticoids (aldosterone) glucocorticoids (cortisol) sex steroids (DHEAS) How Frequent Is Adrenal Insufficiency?
In general, about 40-60 per million individuals have adrenal insufficiency 30,000-34,000 people in U.S.
Public Domain
CC:BY-NC-SA BY: synnwang Types of Adrenal Insufficiency
CRH Hypothalamus TERTIARY (-)
ACTH Pituitary (-) SECONDARY
Cortisol
(+)
Adrenal Gland PRIMARY Adrenal Insufficiency
1ºadrenal 2ºadrenal 2ºadrenal insufficiency insufficiency insufficiency - hypothalamic CRH + - pituitary ACTH
+ adrenal cortisol adrenal aldosterone adrenal pituitary hypothalami c defect defect defect Adrenal Insufficiency: Age Dependent Prevalence
mean age 40 yo (range 17-72 yo) autoimmune adrenalitis most common in all age groups
children: consider PGA or genetic defect young men: adrenoleukodystrophy
adults and elderly: glucocorticoids for non -adrenal diseases Types of Adrenal Insufficiency
CRH Hypothalamus (-)
ACTH Pituitary (-)
Cortisol
(+)
Adrenal Gland PRIMARY PRIMARY Adrenal Insufficiency
CRH Hypothalamus (-)
ACTH Pituitary Public (-) Domain Cortisol Thomas Addison (1793-1860)
(+) Aldosterone Autoimmune adrenalitis (PGA I or II) 80% Adrenal Gland Infections: TB (20% - historically), CMV, fungal Vascular: hemorrhage, thrombosis, arteritis
In cancer patients: metastatic cancer to adrenals In young men: adrenoleukdystrophy
IMPORTANT: In PRIMARY adrenal insufficiency, the adrenals are destroyed, and ALDOSTERONE is affected as well. Adrenal Insufficiency
Autoimmune Adrenal Adrenal Adrenalitis Tuberculosis Hemorrhage
Image of Image of adrenal CC:BY-NC-SA autoimmune tuberculosis BY: University of Alabama at adrenalitis removed Birmingham, Department of Radiology removed
CC:BY-NC-SA BY: University of Alabama at Birmingham, Department of Radiology Metastases in the Adrenal Gland
Skin
Lung Chest
Leukemia Kidney
Ovaries Lymphomas
Public Domain Wikimedia Commons Adrenoleukodystrophy/Adrenomyeloneuropathy
X-LINKED - ONLY IN MALES
PPRESENTATIONRESENTATION -adrenal insufficiency (childhood) -hypergonadotropic hypogonadism (puberty) -spastic paraparesis/demyelination-AMN(20-30 yo) vs cerebral sclerosis-ALD (childhood)
PPATHOPHYSIOLOGY:ATHOPHYSIOLOGY: mutation in Adrenoleukodystrophy protein(ALPD)
ALPD function -pexoxisomal transport protein anchors very long chain AcylCoA synthetase
DDISEASEISEASE - build up of chol. esters w unbranched saturated long chain FAs
TREATMENT: Cortisol replacement Lorenzo’s Oil helps serum level of VLCFA - but no clinical benefit in 3 yr F/U
MUST BE INCLUDED IN w/u of AI in young men and in w/u AI or hypoglycemia in infants Primary Adrenal Insufficiency
Autoimmune adrenalitis results in ADRENAL INSUFFICIENCY
Image of Adrenal Adrenalitis removed
Autoimmune adrenalitis (and therefore its subsequent ADRENAL INSUFFICIENCY) can be found in specific genetic syndromes, POLYGLANDULAR AUTOIMMUNE SYNDROMES Primary Adrenal Insufficiency
PGA I (Polyglandular Autoimmune Syndrome I) autosomal recessive disease- Iranian Jewish heritage starting in childhood
APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) autosomal recessive-Finnish heritage starting in childhood
2 of the following occasionally adrenal insufficiency (<15 yo) chronic active HepB hypoparathyroidism (<10yo) malabsorption chronic mucocutaneous candidiasis (<5 yo) cholelithiosis juvenile onset pernicious PLUS OFTEN anemia dental enamel hypoplasia alopecia/vitiligo keratopathy/ecdodermal dystrophy primary hypogonadism hypothyroidism diabetes mellitus
AIRE (AutoImmune REgulator) Nat Gen 17: 393398; 399-403 Which Twin is Sick????
Image of patients removed Famous Names in Endocrinology
Addison’s Disease
Public Domain Public Domain Wikimedia Commons
John F. Kennedy Jane Austin (1775-1817) Addison’s Disease & History
Public Domain Wikimedia Commons
1960 Presidential Debate John F. Kennedy vs. Richard M. Nixon Chicago, Ill., September 21, 1960 Adrenal Insufficiency
Autoimmune adrenalitis
PGA II usually in middle age females adrenal insufficiency hyothyroidism or diabetes mellitus
*uncertain genetic component autosomal dominant more likely HAL-B8 chromosome 6
PGA III hypothyroidism other autoimmune disorder (NOT adrenal insufficiency) Primary Adrenal Insufficiency
SYMPTOMS
Cortisol • Fatigue • Weakness & Malaise CRH Hypothalamus • Anorexia (-) • Nausea and vomiting ACTH Pituitary (-) Aldosterone Cortisol • Dizziness
(+) Aldosterone
Adrenal Gland SIGNS
• Proximal muscle weakness • Orthostatic hypotension • HYPERPIGMENTATION--Primary AI only • HypoNa, HyperK—Primary AI only Hypoaldosteronism
aldosterone p450c11B2 - 18 ßHSD
cholesterol 18OHCS sTaR p450c11B2 - 18 OH p450scc p450c11B2 3ßHSD p450c21 pregnenolone progesterone DOCS CS
Hypotension Hyperkalemia Hyponatremia Primary Adrenal Insufficiency (ALDOSTERONE DEFECT ONLY SEEN IN PRIMARY AI not SECONDARY AI)
RENAL TUBULE BLOOD
ALDOSTERONE
H+ Aldosterone increases sodium + K resorption and + Na potassium and K+ hydrogen ion Na+ excretion. So, with aldosterone deficiency: Na+ Cl- GluGlu + - K HCO3 Glucocorticoid Deficiency
cholesterol sTaR p450scc 3ßHSD pregnenolone progesterone
7
7
1
1
c c
0 0 17 OH 17 OH 5 17 OH 5
4
4
p p 3ßHSD p450c21 p450c11B1 17OHPregnenolone 17OHprogesterone DOC cortisol
fatigue
hypotension
hypoglycemia DHEAS Deficiency
cholesterol sTaR p450scc 3ßHSD pregnenolone progesterone 17 OH 17 OH
7 7
1 1
c c
0 0 3ßHSD
5 5
4 4 17OHPregnenolone 17OHprogesterone
p p 17,20lyase 17,20lyase 3ßHSD DHEA androstenedione
sulfatase sulfotransferase
DHEAS Male: fatigue, mood Female: fatigue, mood, libidinal dysfunction Adrenal Insufficiency: Hyperpigmentation
Image of Image of patient patient removed hands removed
N Engl J Med Hyperpigmentation of palmar creases 1997;337:1666.
ACTH
Public Domain T. Addison “On the constitutional and MSH local effects of disease of the Source: Undetermined suprarenal capsules” 1855 Types of Adrenal Insufficiency
CRH Hypothalamus (-) ACTH Pituitary SECONDARY (-)
Cortisol
(+)
Adrenal Gland Types of Adrenal Insufficiency
CRH Hypothalamus TERTIARY (-) ACTH Pituitary (-)
Cortisol
(+)
Adrenal Gland Secondary & Tertiary Adrenal Insufficiency
CRH Hypothalamus (-) Vascular: Postpartum necrosis(Sheehan’s)
ACTH Pituitary Lymphocytic hypophysitis (-) Infiltrative diseases: Sarcoidosis, Histiocytosis X Cortisol Tumor compression Following surgery or radiation
(+) Long term glucocorticoid treatment Pharmacologic Dose = more than physiologic replacement Adrenal Gland Secondary Adrenal Insufficiency
CRH Hypothalamus SYMPTOMS (-) SYMPTOMS ACTH Pituitary (-) • Mild malaise, fatigue Cortisol • Proximal muscle weakness
(+) Aldosterone SIGNS
Adrenal Gland • NO hyperpigmentation • NO orthostatic hypotension
SIGNS & SYMPTOMS are generally milder than with primary adrenal insufficiency due to cortisol deficiency ALONE (ie: NO ALDOSTERONE DEFICIENCY) Adrenal Insufficiency
REMEMBER TO DIFFERENCE BETWEEN PRIMARY AI AND SECONDARY AI
PRIMARY ONLY SECONDARY ONLY hyperpigmentation (92-96%) HYPERkalemia (52-64%) associated features (ie can see if PGA) associated features (ie can see if entire pit. involvedinvolved
vitiligo (4%) growth delay hypothyroidism (primary) HA hypogonadism (primary) DI (if stalk involved) hypothyroidism (secondary) hypogonadism (secondary) Adrenal Crisis
*hemorrhage thromboembolic disease Coagulopathy anticoagulant therapy Waterhouse-Friderichsen Syndrome Neisseria meningitidis septicemia Streptococcus pneumoniae, Pseudomonas aeruginosa Staphylococcus aureus Escherichia coli Haemophilus influenzae *drugs - increase metabolism GC phenytoin, phenobarbitol, rifampin *drugs - decrease production GC ketoconazole, AG, mitotane, metyrapone
*withdrawal of exogenous glucocorticoids Adrenal Crisis
suspect in setting of: look for: catecholamine resistant hypotension hyperpigmentation/decreased pubic hair hypotension with abd pain hyperkalemia must r/o adrenal hemorrhage hyponatremia hypoglycemia
If the diagnosis is missed, your patient will most likely die Adrenal Insufficiency Diagnostic
SCREENING TEST:
AM CORTISOL: GOAL is to RULE OUT disease
PPrinciplerinciple of test: Cortisol is highest in the AM allowing maximal chance of ruling out disease
-HI AM cortisol RULES OUT DISEASE
-BUT ONLY EXTREMELY LOW AM cortisol is DIAGNOSTIC
MMostost patients are neither EXTREMELY HI or EXTREMELY LOW and require DYMANIC testing Adrenal Insufficiency Diagnostic
DIAGNOSTIC TEST FOR PRIMARY ADRENAL INSUFFICIENCY:
ACTH STIMULATION TEST: GOAL is to RULE IN disease
Principle of test: ACTH stimulates steroidogenesis and secretion of cortisol - normal levels well documented
-Cortisol level after ACTH that is SUBNORMAL is DIAGNOSTIC of AI
-ACTH level that is EXTREMELY HI is CONSISTENT with diagnosis of PRIMARY AI but is NOT DIAGNOSTIC The ACTH Stimulation Test
CRH Hypothalamus CRH Hypothalamus (-)
ACTH Pituitary ACTH (-) Pituitary
No Low or blunted serum Cortisol Cortisol increasecortisol in serum cortisol (+) (+)
Adrenal Adrenal Gland Gland
NORMAL ADRENAL INSUFFICIENCY Synthetic ACTH (Cosyntropin) Adrenal Insufficiency Diagnostic
DIAGNOSTIC TEST FOR SECONDARY ADRENAL INSUFFICIENCY:
INSULIN HYPOGLYCEMIA TEST: GOAL is to RULE IN disease
Principle of test: Insulin results in hypoglycemia that is the strongest stimulus for activation of HPA axis at the level of CRH
Cortisol level after IHT that is SUBNORMAL is DIAGNOSTIC of AI
ACTH level after IHT that is SUBNORMAL is DIAGNOSTIC of SECONDARY AI Diagnosis of Secondary/Tertiary Adrenal Insufficiency
The Insulin Tolerance Test
CRH Hypothalamus INSULIN (-)
ACTH Pituitary (-)
Cortisol Insulin-induced hypoglycemia is a powerful stimulus of the (+) HPA axis
Adrenal Gland Therapy for Adrenal Insufficiency
Therapy
Image of Image of adrenal adrenal gland gland removed removed
Public Domain Public Domain
1543 1564 Guidelines for Management
GUIDING PRINCIPLE: The more severe the stress the more cortisol patient needs
Acute Therapy (significant ill or Adrenal Crisis)
IV fluids Do not wait for labs!!!! IV cortisol: HI DOSE glucose treat underlying precipitating events
Maintenance Therapy Glucocorticoids hydrocortisone ~ 15-25 mg/d titrate to a sense of well being and physical strength avoid weight gain, hypertension, hyperglycemia and osteoporosis Mineralocorticoids fludrocortsone ~0.1 mg/d titrate to salt craving and postural hypotension together with serum K and upper range renin DHEA - Guidelines for Management
GUIDING PRINCIPLE: The more severe the stress the more cortisol patient needs!
Stress Dosing Glucocorticoids
MMinimalinimal no need for supplemental coverage dental work mild or non-febrile illness
Minor 25 mg hydrocortisone - day of procedure (or onset of fever) hernia repair
MModerateoderate 50-75 mg hydrocortisone - day of procedure (or onset of fever) hemicolectomy rapid taper in 1-2 days significant febrile illness
Severe 100-150 mg hydrocortisone - day of procedure (or onset of fever) cardiac surgery rapid taper in 1-2 days
Critically ill 100 mg hydrocortisone i.v. bolus followed by - sepsis 50-100 mg hydrocortisone i.v. q 6-8 hours (or 0.18 mg/kg/hr) 0.05 mg/d fludrocortisone until shock resolves (days to week Discontinuing Glucocorticoids Following Long Term Suppression
GUIDING PRINCIPLE: The more glucocorticoid and the longer treated - the greater chance of long term suppression and atrophy of HPA axis
risk of suppression Low risk: Low dose, short duration or short “bursts” of glucocorticoid High dose and prolonged therapy ( 1-4 weeks) - risk is higher
time course for recovery Larger doses for prolonged periods (months - years) - recovery can take from 9 MONTHS up to 1-2 years
need for taper taper from pharmacologic to physiologic (determined by non-adrenal disease course) taper from physiologic to no treatment (determined by adrenal suppression) DHEA: What is all the fuss?
Marker of aging -??pharmacologic reversal of aging process??
Predictor of morbidity/mortality
Works wonders in rodents -CNS, obesity, diabetes, immunity
Preliminary studies in humans DHEA what is it??
19 carbon (androstane) 5,3-hydroxy,17-keto S04, ester at 3
Source: Undetermined Synthesized by adrenals only in humans and higher primates -obligate precursor of all sex steroids in humans
More synthesized than all other steroids -up to 25 mg/day in adults -major secretion of fetal adrenal
Most secreted as sulfate (DHEA-S) -sulfation is ONLY in ADRENAL (NOT GONAD)
Inactive at androgen receptor DHEA: How Does it Work?
Conversion to androgens -50 mg/d raises testosterone in females
Intrinsic activity of DHEA-S in brain -trophic effects on cultured neurons -GABA, NMDA, sigma receptor-channels
Actions of weird metabolites -concept of NEUROSTEROIDS Case for DHEAS
DHEA + DHEAS major secretory products of adrenal peak in fetal life and adrenarche
Decline throughout adult life to 20-20% by 70-80 yo
Source: TRENDS Advertisement as ANTI-AGING drug In USA : FOOD SUPPLEMENT!!!!!
classic steroid converted to testosterone peripherally neurosteroid directly binding NMDA + GABA receptors Images of DHEA removed Case for DHEAS
Source: TRENDS DHEA in men and women with primary adrenal insufficiency improves mood and well-being, irrespective of the patient's sex.
Source: TRENDS DHEA replacement in women with adrenal insufficiency improved overall well-being and mood, specifically depression, anxiety and both sexual interest and sexual satisfaction. Guidelines for DHEA Treatment in Adrenal insufficiency
Adrenal Androgens only in pts w AI who do NOT feel “normal on replacement GC and MC”
DHEA: 25 mg po q a.m.
-may increase to 50 mg -dictated by response and androgenic side effects -monitor labs DHEAS, androstendione and free test LFTS and lipids at 4 + 12 w Watch Out for Supplements
Steroids are lipophilic Undetermined dosing Undetermined purity
Image of Raw Image of Adrenal Image of Adrenal Adrenal Glandular Plus Glandular Plus Supplements Supplements Supplements removed removed Image of Adrenal Cortex Complex Supplements removed Congenital Adrenal Hyperplasia
Hypothalamus CRH • Genetic block in biosynthetic pathway (-) for cortisol and aldosterone result in primary adrenal insufficiency. ACTH Pituitary (-) • Decreased feedback on hypothalamus Cortisol and pituitary increase CRH and ACTH.
(+) • Increased ACTH further stimulates adrenals and results in shunting and production of precursors. Adrenal Gland • ACTH stimulates growth (HYPERPLASIA) of adrenals. Steroidogenesis
glomerulosa
fasciculata
reticularis
gonad periphery
Public Domain Wikimedia Commons Steroidogenesis
glomerulosa
fasciculata
reticularis
gonad periphery
Public Domain Wikimedia Commons Steroidogenesis
glomerulosa
fasciculata
reticularis
gonad periphery
Public Domain Wikimedia Commons SEVERE P45c21 Deficiency in FEMALE
Image of patient removed
results in androgen excess in utero MILD P45c21 Deficiency in FEMALE
Beard
CC:BY-NC-SA 1.0 BY: C. Matthew Peterson, MD
CC:BY-NC-SA 1.0 BY: C. Matthew Peterson, MD
Cliteromegaly
Hirsuitism
results in androgen excess at puberty Congenital Adrenal Hyperplasia
Important things to remember: • Loss of function of enzyme in steroidogenesis pathway
• “Block” in pathway leads to shunting down alternate paths and abnormal build-up precursors before the block.
• Severe forms lead to virulization of females
• Milder forms (“non-classical”) may lead to hirsuitism and menstrual abnormalities in women.
• Block in pathway may result in adrenal insufficiency during times of stress. Adrenal Excess States Causes of hypercortisolism
Physiological states Pathologic states • Pregnancy Cushing's syndrome Diabetes mellitus • Stress Hyperthyroidism • Chronic excessive exercise Severe chronic disease • Malnutrition Glucocorticoid resistance Psychological states Anorexia nervosa Panic disorder Melancholic depression Obsessive-compulsive disorder
PHARMACOLOGIC USE OF GLUCOCORTICOIDS Cushing’s Syndrome
Public Domain Public Domain Harvey Cushing (far left) in 1895 during his DR. HARVEY WILLIAMS CUSHING House Pupilship (internship) at (1869-1939) Massachusetts General Hospital.
Cushing HW. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital. 1932;50:137-95
His research on the pituitary body gained him an international reputation, and he was the first to ascribe to pituitary malfunction a type of obesiobesityty of the face and trunk now known as Cushing's disease, or Cushing's syndrome. Cushing‘s Syndrome
All types of Cushing’s Syndrome HI CORTISOL (urine and serum) Absent circadian rhythm
Adrenal Cushing’s syndrome is autonomous and therefore has LOW ACTH Only ACTH-dependent Cushing’s (by definition) has HI ACTH Cushing’s Syndrome
ACTH independent Cushings ACTH dependent Cushing s pituitary ectopic ectopic adrenal ACTH ACTH CRH Cushing s Cushing s Cushing s Cushing s
- hypothalamic CRH ectopic + CRH - pituitary ACTH ectopic ACTH + adrenal cortisol adrenal pituitary ectopic defect defect defect Cushing’s Syndrome
Exogenous GC administration Pituitary adenoma
ACTH-dependent Ectopic ACTH Endogenous (CRH) syndrome hypercortisolism
Adrenal ACTH- adenoma independent Adrenal carcinoma Cushing’s Syndrome
ACTH-dependent Cushing’s Syndrome pituitary adenoma-ACTH (60%) Image of pituitary Ectopic hormone (10%) glands removed ACTH CRH
all result in bilateral adrenal hyperplasia Types of Cushing’s Syndrome
PITUITARY Hypothalamus ADENOMA CRH (-) Cushing’s Disease ACTH Pituitary (“pituitary Cushings”): (-) hypercortisolism from a pituitary adenoma Cortisol HARVEY
(+)
Adrenal Gland
Public Domain Normal Pituitary
GNU Free documentation license version 1.2 Wikimedia Commons
Source: Undetermined Pituitary Cushing‘s DISEASE
Source: Undetermined normal Source: Undetermined Cushing’s disease Ectopic Cushing’s
Hypercortisolism from CRH Hypothalamus Ectopic production of (-) ACTH or CRH by tumor. ACTH Pituitary (-) Cortisol Images of oat cell in lung removed ACTH Causes • Bronchial carcinoid • Oat cell carcinoma • Thymic carcinoid • Pheochromocytoma Small (Oat) cell ca of lung Adrenals • Medullary thyroid ca Cushing’s Syndrome
ACTH-independent Cushing’s Syndrome adrenal cortical neoplasm adenoma carcinoma primary adrenal hyperplasia
CC:BY-NC-SA 1.0 BY: Cornell University Adrenal Cushing’s
Adrenal Causes: CRH Hypothalamus Hypercortisolism from a (-) adrenal adenoma or carcinoma ACTH Pituitary (-) Cortisol Because ACTH is suppressed, the rest of the adrenal and contralateral (+) gland are atrophied.
Adrenal Contralateral Adrenal Adrenal adenoma or carcinoma Cushing’s Syndrome
CLINICAL MANIFESTATIONS of CORTISOL EXCESS
increased protein catabolism = striae, bruising, delayed wound healing, muscle wasting
increased glucose production = DM
redistribution of fat = truncal obesity ACTH dependent ONLY Pigmentation (MSH) bone breakdown = osteoporosis ACTH dependent or Mixed Adrenal facilitation of catechol synthesis = hypertension Androgen excess Terminal hair hirsuitism anti-inflammatory = opportunistic infections Acne Inhibition of HPG axis = amenorrhea, impotence Irregular menses balding CNS effects(limbic/hippocampus) = depression and memory difficulties Cushing‘s Syndrome
Physical examination: adiposity moon face, plethora (pseudo-) gynecomastia striae
Image of patient Image of patient with moon face / with striae on arms plethora removed removed Cushing‘s Syndrome
Acanthosis nigricans Purple striae
Image of patient Image of patient Image of patient with acanthosis with striae on with striae on nigricans on armpit abdomen removed abdomen removed removed Cushing‘s Syndrome
Myopathy Proximal muscle wasting Images of myopathic Osteoporosis patient removed Oligo-Amenorrhea/Impotence Psychiatric Symptoms depression, mania (Steroid psychoses) ACTH-Dependent Pituitary Cushing‘s Disease
Symptoms due to pituitary mass bitemporal hemianopsia pituitary insufficiency HA Cushing‘s Syndrome: Diagnosis
Diagnosis First diagnose CORTISOL EXCESS elevated 24 hr urine cortisol < 100 mg/24 hr
Then diagnose PATHOLOGIC CORTISOL EXCESS r/o physiologic causes which suppress normally with low-dose DEX (Cort < 5 mg/dl)
ACTH dependent or NOT Measure ACTH level if DETECTABLE > 9 pg/ml - must be ACTH dependent (if NOT DETECTABLE < 9 pg/ml - must be ACTH independent) Cushing’s Syndrome: Low-dose DEX suppression
Low- Dose Dose CRH Hypothalamus DEX (-)
ACTH Pituitary ACTH (-)
Cortisol Ectopic tumor
(+) ACTH
Adrenal Gland
Low-dose Dex will suppress ACTH secretion in: -normal patients -physiologic hypercortisolism (stress)
Low-dose Dex will NOT suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (pituitary adenoma or ectopic ACTH producing tumors) -ACTH independent Cushing’s syndrome (adrenal tumors) Cushing‘s Syndrome: Diagnosis
Diagnosis First diagnose CORTISOL EXCESS elevated 24 hr urine cortisol < 100 mg/24 hr
Then diagnose PATHOLOGIC CORTISOL EXCESS r/o physiologic causes which suppress normally with low-dose DEX (Cort < 5 mg/dl)
ACTH dependent or NOT Measure ACTH level if DETECTABLE > 9 pg/ml - must be ACTH dependent (if NOT DETECTABLE < 9 pg/ml - must be ACTH independent) ACTH-DEPENDENT Cushing’s Syndrome
Is it pituitary or ectopic????
High dose DEX SUPPRESSION TEST Pituitary Cushing’s may suppress to high dose DEX Ectopic NEVER suppresses to high dose DEX
Inferior Petrosal sinus Sampling Pituitary Cushing’s - find HI ACTH near pituitary and low in the periphery Ectopic Cushing’s - find HI ACTH in the periphery and low near pituitary
IMAGE the pituitary Cushing’s Syndrome: Hig-dose DEX suppression
HIGH- Dose Dose CRH Hypothalamus DEX (-)
Most pituitary adenomas that ACTH Pituitary secrete ACTH can still be (-) inhibited by REALLY REALLY ACTH HIGH glucocorticoids (ie more that produced their Cortisol diseased HPA axis)
Therefore, HIGH-dose dexamethasone will NOT (+) suppress ACTH from ectopic tumors. Adrenal Gland
High-dose Dex will suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (pituitary adenoma)
High-dose Dex will NOT suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (ectopic tumors) Cushing’s Syndrome: Diagnosis
HIGH- Dose Dose CRH Hypothalamus DEX (-)
Pituitary Most ectopic ACTH- ACTH producing tumors secrete (-) ACTH independently from regulation by glucocorticoids. Cortisol Cortisol Ectopic Therefore, HIGH-dose tumor dexamethasone will NOT suppress ACTH from ectopic tumors. (+) ACTH
Adrenal Gland
High-dose Dex will suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (pituitary adenoma)
High-dose Dex will NOT suppress ACTH secretion in: -ACTH dependent Cushing’s syndrome (ectopic tumors) Imaging in Cushing Syndrome
ADRENAL CT findings Pit MRI findings adrenals small = ? Mass or no mass one adrenal large and 1 small =? (some pituitary corticotrope Both adrenals large=? tumors are too small to be seen on MRI)
Search for ectopic ACTH or CRH producing tumor Lung: Bronchial Carcinoid and SCC 50% Thymic Carcinoid (epithelial thymoma 10% Pancreatic Islet Cell Tumor 10% Pleochromocytoma 10% Abdominal Carcinoids 5% Medullary Thyroid Carcinoma 5% Cushing’s Syndrome Treatment
adrenal adenoma pituitary adenoma resection transphenoidal resection (TSR) cortisol replacement cortisol replacement if not curative if not curative XRT XRT bilateral adrenalectomy bilateral adrenalectomy adrenolytic therapy adrenolytic therapy mitotane mitotane ketoconazole mitotane ketoconazole
Ectopic ACTH or CRH Find the tumor!!!!!!!!!!! if not curative bilateral adrenalectomy adrenolytic therapy mitotane ketoconazole Cushing‘s Syndrome
Image of patient before treatment with Cushing’s Syndrome removed
Image of patient with Cushing’s after treatment Syndrome removed Cushing‘s Syndrome
Public Domain Wikimedia Commons Public Domain Wikimedia Commons CC:BY 2.0 BY: tajai
dogs Ferrets horses UM Endocrinology in Adrenal History: Conn Syndrome
Image of Jerome Image of patient Conn removed removed
CC:BY 2.0 BY: Michael Feldman, MD Jerome Conn, M.D.
Conn JW. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3-17 Primary Aldosteronism
Clinical Presentation Manifestations of HYPOKALEMIA and HTN LOW K neuromuscular paresthesias weakness tetany Renal Polyuria Carbohydrate abnormal GTT HTN usually not malignant early in disease may have HTN with NORMAL K Causes of Hyperaldosteronism
Definition: syndrome of inappropriate excessive secretion of aldosterone by adrenal gland kidney (JGA) renin IVV + Na + IVV + + K angiotensinogen angiotensin a ngiotensin II + AII-R ----> aldosterone + MR H liver adrenal + (glomerulosa) K (serum) ACE met alk lung kidney (distal tubule)
Source: Undetermined
An increase in aldosterone ACTION can theoretically result from ANY defect in RAA pathway
-LOW IVV (real or perceived by kidney in renal artery stenosis) -JGA renin tumor -ACE polymorphisms -overproduction of AII by renal tumors -ADRENAL overproduction of ALDO -constitutive MR or Na channel Primary Aldosteronism
primary hyperaldosteronism (HI ALDO/LOW RENIN) ZG Aldo tumor 70% ZG Aldo hyperplasia 30%
rare/rare/rare Congenital adrenal hyperplasia <1% (p450c11ß, p450c17) ACE polymorphisms < 1% AII overproduction < 1%
secondary hyperaldosteronism (HI ALDO/HI RENIN) JGA renin tumor <1% renal artery stenosis <1%
apparent mineralocorticoid excess (LOW ALDO/LOW RENIN) (downstream of ALDO) constitutively active MR <1% Na/K/H channel <1% licorice <1% Primary Aldosteronism
Consider in patients with:
-New HTN -HTN with LOW K
EVEN THOUGH it only accounts for 0.5% of all HTN
BECAUSE-BECAUSE- IFIF YOUYOU NEVERNEVER THINKTHINK OFOF THIS--THIS-- ---YOU---YOU WILLWILL NEVERNEVER FINDFIND IT!!!IT!!! Primary Aldosteronism
Work-Up R/O other causes of LOW K LOW intake (diet) HI output N/V/D Diuretic use with loops + thiazides
24 h Urine ALDO If LOW- pt does not have PRIMARY ALDO IF HI (>10 ug/day) check RENIN level (suppressed < 1 ng/ml/hr) If RENIN HI ----JGA renin tumor or RAS If RENIN LOW---- PRIMARY HYPERALDO
IF NECESSARY (ie AMBIGUOUS) Volume expand to see if can suppress RAA If can suppress --essential HTN Adrenal Zona Glomerulosa Adenoma
Image of Adrenal gland removed Primary Aldosteronism
IMAGING and TREATMENT CT scan Adenoma unilateral ADX NO adenoma selective venous cath to measure ALDO rt vs lt If unilateral elevation-small adenoma If no lateralization-bilateral hyperplasia Medical trt with spironolactone or amiloride bilateral ADX Adrenocortical Carcinoma
Larger adrenal mass
High probability NOT benign if >5 cm in diameter
Image of Adrenal Development of Cushingoid gland removed features usually very rapid (several months rather than years)
Often associated with elevated DHEA-sulfate and virulization Remember:
EndocrineEndocrine disordersdisorders areare NOTNOT diagnoseddiagnosed byby meansmeans ofof imaginingimagining studies.studies. BiochemicalBiochemical conconfifirmationrmation mustmust comecome fifirstrst beforebefore imaginingimagining isis performed.performed. Public Domain Wikimedia Commons “Even our destiny is determined by our endocrine glands.”
Albert Einstein